Improved methods to simultaneously deliver drugs and genes are needed to fully realize the potential of drug-gene combination therapies. Our long-term goal is to establish a new class of biodegradable gene delivery vectors capable of functioning dually as (i) gene delivery vectors and (ii) active pharmacologic agents after intracellular degradation. The objective of this proposal is to design innovative biodegradable dendritic BENSpm polycations (BDBP) capable of functioning dually as a gene delivery vector and an active anticancer agent targeting dysregulated polyamine metabolism in cancer. We will develop biodegradable dendrimer prodrugs based on a cationic drug N1,N11-bis(ethyl)norspermine (BENSpm) that will efficiently deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene to triple negative breast cancer cells and then decompose into the original drug BENSpm, thus augmenting the therapeutic effect of TRAIL. We hypothesize that the combined drug-gene delivery will improve TRAIL anticancer activity due to synergistic enhancement by BENSpm released from BDBP, as suggested by our preliminary data. Our overall objective will be achieved by pursuing two specific aims: 1) synthesize biodegradable dendritic BENSpm polycations; 2) determine whether BDBP combined with TRAIL enhances antiproliferative activity in human breast cancer. In aim 1, a synthetic methodology, which has been established as feasible by the applicant will be used to prepare BDBP that are degradable in a reducing intracellular environment and capable of releasing intact BENSpm. In aim 2, the BDBP will be used to deliver TRAIL-GFP plasmid in triple-negative breast cancer cells, MDA-MB-231, and to evaluate the effect of intracellular BDBP degradation and BENSpm release on the antiproliferative activity of expressed TRAIL-GFP in 3-D culture. The approach is innovative because of the novel design of delivery vectors that not only deliver therapeutic genes but also augment the activity of the therapeutic gene by exerting its own pharmacologic effect. The proposed research is significant because it will establish a widely applicable design paradigm for non-viral gene delivery systems for simultaneous drug-gene delivery and thus it will improve outcome of gene therapy strategies.